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Naproxen, an anti-inflammatory drug, exhibits poor aqueous solubility, which limits the pharmacological
effects. The present work was carried out to study the effect of agglomeration on micromeritic properties
and dissolution. Naproxen agglomerates were prepared by using a three solvents system composed of
acetone (good solvent), water (non-solvent) and dichloromethane (bridging liquid). Differential Scanning
Calorimetry (DSC) results showed no change in the drug after crystallization process. X-Ray Powder
Diffraction (XRPD) studies showed the sharp peaks are present in the diffractograms of spherical
agglomerates with minor reduction in height of the peaks. The residual solvents are largely below
the tolerated limits in the agglomerates. Scanning Electronic Microscopy (SEM) studies showed that
agglomerates were spherical in structure and formed by cluster of small crystals. The agglomerates
exhibited improved solubility, dissolution rate and micromeritic properties compared to pure drug.
Anti-inflammatory studies were conducted in Wistar strain male albino rats and naproxen agglomerates
showed more significant activity than the pure drug.
Uniterms: Naproxen/micromeritic properties. Naproxen/spherical agglomerates/dissolution. Residual
solvents. Ulcerogenic potential. Bridging liquid.
Naproxeno, frmaco anti-inflamatrio, apresenta baixa solubilidade em gua, o que limita os efeitos
farmacolgicos. O presente trabalho foi realizado para estudar o efeito da aglomerao nas propriedades
micromerticas e na dissoluo. Aglomerados de naproxeno foram preparados por meio da utilizao
de sistema de trs solventes composto de acetona (bom solvente), gua (no-solvente) e diclorometano
(lquido de ligao). A DSC no resulta mostrou nenhuma mudana na droga depois de processo de
cristalizao. Estudos de difrao de Raios X do P (XRPD) mostraram picos agudos nos difratogramas
de aglomerados esfricos, com reduo mnima dea altura dos picos. Os solventes residuais esto
amplamente abaixo dos limites tolerados nos aglomerados. Os estudos de Microscopia Eletrnica de
Varredura (SEM) mostraram que esses aglomerados eram de estrutura esfrica e formados por grupos
de pequenos cristais. Os aglomerados apresentaram solubilidade, taxa de dissoluo e propriedades
micromerticas aprimoradas em comparao com o frmaco puro. Estudos anti-inflamatrios foram
conduzidos em ratos Wistar albinos masculinos e os aglomerados de naproxeno mostraram atividade
mais significativa do que o frmaco puro.
Unitermos: Naproxeno/propriedades micromerticas. Naproxeno/aglomerados esfricos/dissoluo.
Solventes residuais. Potencial ulcerognico. Lquido de ligao.
Article
Brazilian Journal of
Pharmaceutical Sciences
vol. 48, n. 4, oct./dec., 2012
668
INTRODUCTION
Recently the direct tablet compression method is
frequently and preferably used for tablet manufacturing,
since many processing steps (granulation, drying etc) are
eliminated and in addition wet technology can not be used
to moisture sensitivity agents (effervescent tablets) (Maghsoodi et al., 2007). In the direct tabletting method, it is
necessary to increase the flowability and compressibility of
the bulk powder in order to retain a steady supply of powder
mixture to the tabletting machine and sufficient mechanical
strength of the compacted tablet. In addition to increasing
the efficiency of the manufacturing process it is also important to increase bioavailability of the drug by improving the
solubility of the bulk drug powder. Spherical agglomeration
is a novel method to increase the bioavailability of the drug
that inherently has poor aqueous solubility. It is a multiple
unit process in which crystallization, agglomeration and
spheronization can be carried out simultaneously in one step
(Kulkarni et al., 2002). The resultant crystals have characteristic shape which dramatically improved the micromeritic
properties such as flowability, packability and compressibility so that direct tabletting or coating is possible without
further processing (mixing, agglomeration, sieving).
Spherical agglomeration is a process of formation
of aggregates of crystals held together by liquid bridges.
The agglomerates are formed by agitating the crystals in a
liquid suspension in presence of binding agent. The bridging liquid should be immiscible in the suspending medium,
but capable of cementing the particles to be agglomerated.
This technique can also be exploited to increase solubility,
dissolution and hence bioavailability of poorly soluble
drugs (Di Martino, 1999; Sano, 1987; Kawashima et al.,
1990). These modifications allow for the practice of more
efficient manufacturing methods that could save time and
reduces economic risk.
Naproxen is an anti-inflammatory drug which exhibits poor water solubility and unsuitable for direct tabletting due to its poorly compressible properties, although
strongly demanded in commercial production by direct
tabletting. It exhibits poor flow, and a high tendency of
adhesion. To improve the micromeritic properties, dissolution rate and bioavailability, spherical crystallization
method is attempted.
Improved dissolution and micromeritic properties of naproxen from spherical agglomerates: preparation, in vitro and in vivo characterization
Particle size of pure drug was determined by microscopic method using calibrated ocular micrometer and
size of spherical agglomerates was determined by sieving
method [8]. Apparent particle densities of agglomerated
and pure drug were measured using a Pycnometer (Gay
Lussac, India). Carrs index was determined from powder volumes at the initial stage and after 1250 tappings
to constant volume (Electrolab, Mumbai). The angle of
repose of agglomerated and pure drug was measured by
fixed funnel method.
Crushing strength
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Residual water in spherical agglomerates was determined using Karl Fischer (Polmon, Hyderabad, India)
titrimeter, calibrated with sodium tartrate. Gas chromatography (Shimadzu GC-14B chromatograph, Japan) was
used to estimate residual Acetone and dichloromethane in
spherical agglomerates (Piera Di Martino et al., 2000).
Solubility studies
670
Healthy Wistar strain male albino rats weighing between 150 200 g were used for the study and individually
maintained under standard conditions (12 h light and dark
cycles, 25 22 oC and 3560% humidity). The rats were
fed with animal fed pellets and had free access to water.
The rats were divided into three groups each containing 6 animals that are controlled (group-1), standard
(group-2) and test group (group-3). Animals were kept
under fasting with free access to water for 48 h before
Improved dissolution and micromeritic properties of naproxen from spherical agglomerates: preparation, in vitro and in vivo characterization
671
Drug content
The melting point of naproxen pure drug and agglomerates was found to be in the range 150 C -155 C
and was observed that there was no change in melting
points of pure drug and agglomerates. Thus, formation
of polymorphs was over ruled, as crystal habit will not
change the melting point.
Differential scanning calorimetry (DSC)
DSC thermograms of pure and naproxen agglomerates are illustrated in Figure 1. The DSC pattern of pure
naproxen and agglomerates showed a sharp endothermic
peak at 153 C corresponding to its melting point. Sharp
melting point with flat base line, which indicated that the
material was not affected by hydration, solvation, polymorphic transition and in addition there was no interaction
of drug with solvents.
X-ray analysis
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Improved dissolution and micromeritic properties of naproxen from spherical agglomerates: preparation, in vitro and in vivo characterization
673
FIGURE 3 - SEM of A: naproxen pure drug, B: agglomerate, C: surface of the agglomerate. The powder was irregularly shaped
(A) and spherical agglomerates were obtained after the successful completion of experiment (B). The surface of the spherical
agglomerate (C) shows that the minute particles of the drug have agglomerated to give a spherical shape.
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agglomerates
Properties
Pure Drug
5-10
Agglomerates
830 (Average
particle size)
11.23 0.93
46 0.79
0.349 0.14
0.237 0.43
32.09
0.974 1.37
Residual solvent
Concentration
(ppm)
0.912 0.23%
4.2036 1.458
3.561 2.14
Concentration limit
(ppm)*
5000
600
Water
Acetone (Class III)
Dichloromethane
(Class II)
*As per ICH guide lines. Values are average of 3 determinations
(n = 3)
Anti-inflammatory activity and ulcerogenic potential were carried out for pure naproxen and agglomerates.
Table IV shows the results of paw edema and percentage
inhibition of carrageenan-induced paw edema in rats
treated with pure naproxen and naproxen agglomerates. An
extremely significant (p<0.001) inhibition of carrageenan
induced paw edema was observed in animals treated with
naproxen agglomerates in comparison with control during
the entire 3 h duration of the study, significant (p<0.05) in-
Improved dissolution and micromeritic properties of naproxen from spherical agglomerates: preparation, in vitro and in vivo characterization
675
Time (h)
5
5
5
CONCLUSION
Naproxen agglomerates that were prepared by simple
spherical crystallization technique exhibited improved micromeritic properties and dissolution rate. DSC and XRD
study showed that there is no change in the crystal structure
and polymorphism was not occurred. Due to the significant
improvement of micromeritic properties, this technique
may be used for formulation of naproxen tablets by direct
compression method. The agglomerates were found to be
having better anti-inflammatory activity in the rats when
compared to pure drug due to improved solubility.
% Inhibition
--39.132.16
65.212.85
REFERENCES
AULTON, M. E.. Aultons Pharmaceutics the design and
manufacture of medicine. 3.ed. London: Churchill
Livingstone Elsevier, 2007. p.355-357.
DI MARTINO, P.; BARTHELEMY, C.; PIVA, F.; JOIRIS, E.;
PALMIERI,G.F.; MARTELLI, S. Improved dissolution
behavior of fenbufen by spherical crystallization. Drug Dev.
Ind. Pharm., v.25, n.10, p.1073-1081, 1999.
DI MARTINO, P.; DI CRISTOFARO, R.; BARTHELEMY,
C.; JOIRIS, E.; PALMIERI FILIPPO, G.; SANTE, M.
Improved compression properties of propyphenazone
spherical crystals. Int. J. Pharm., v.197, n.1-2, p.95-106,
2000.
INDIAN PHARMACOPOEIA. The Indian Pharmacopoeia
commission. 6.ed. PA: Ghaziabad, 2010. v.3, p.1754-1758.
KULKARNI, P.K.; NAGAVI, B.G. Spherical crystallization.
Ind. J. Pharm. Educ., v.36, n.5, p.66-73, 2002.
KULKARNI, S.K. Hand book of experimental pharmacology.
3.ed. New Delhi: Vallabh Prakashan, 2002. 149 p.
LICHTENBERGER, M.; ROMERO, J.J.; DIAL, E.J.; MOORE,
J.E. Naproxen-PC: A GI safe and highly effective antiinflammatory. Inflammopharmacology, v.17, n.1, p.1-5,
2009.
ACKNOWLEDGEMENTS
MAGHSOODI, M.; HASSAN-ZADEH, D.; BAZEGARJALALI, M. Improved compaction and packing properties
of naproxen agglomerated crystals obtained by spherical
crystallization technique. Drug Dev. Ind. Pharm., v.33, n.1,
p.1216-1224, 2007.
The authors are thankful to M/S Divis Labs, Hyderabad, India for the gift sample of Naproxen. We also
thank the Quality Assurance Deputy Manager, Macleods
Pharmaceuticals, Vapi, Gujarat for gas chromatographic
analysis.
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